The present invention relates to peroxisome proliferator activator receptor (PPAR) agonists, in particular, PPARα agonists, pharmaceutical compositions containing such agonists and the use of such agonists to treat atherosclerosis, hypercholesterolemia, hypertriglyceridemia, diabetes, obesity, osteoporosis and Syndrome X (also known as metabolic syndrome) in mammals, including humans.
Atherosclerosis, a disease of the arteries, is recognized to be the leading cause of death in the United States and Western Europe. The pathological sequence leading to atherosclerosis and occlusive heart disease is well known. The earliest stage in this sequence is the formation of “fatty streaks” in the carotid, coronary and cerebral arteries and in the aorta. These lesions are yellow in color due to the presence of lipid deposits found principally within smooth-muscle cells and in macrophages of the intima layer of the arteries and aorta. Further, it is postulated that most of the cholesterol found within the fatty streaks, in turn, gives rise to development of the “fibrous plaque,” which consists of accumulated intimal smooth muscle cells laden with lipid and surrounded by extra-cellular lipid, collagen, elastin and proteoglycans. These cells plus matrix form a fibrous cap that covers a deeper deposit of cell debris and more extracellular lipid. The lipid is primarily free and esterified cholesterol. The fibrous plaque forms slowly, and is likely in time to become calcified and necrotic, advancing to the “complicated lesion,” which accounts for the arterial occlusion and tendency toward mural thrombosis and arterial muscle spasm that characterize advanced atherosclerosis.
Epidemiological evidence has firmly established hyperlipidemia as a primary risk factor in causing cardiovascular disease (CVD) due to atherosclerosis. In recent years, leaders of the medical profession have placed renewed emphasis on lowering plasma cholesterol levels, and low density lipoprotein cholesterol in particular, as an essential step in prevention of CVD. The upper limits of “normal” are now known to be significantly lower than heretofore appreciated. As a result, large segments of Western populations are now realized to be at particularly high risk. Additional independent risk factors include glucose intolerance, left ventricular hypertrophy, hypertension, and being of the male sex. Cardiovascular disease is especially prevalent among diabetic subjects, at least in part because of the existence of multiple independent risk factors in this population. Successful treatment of hyperlipidemia in the general population, and in diabetic subjects in particular, is therefore of exceptional medical importance.
In spite of the early discovery of insulin and its subsequent widespread use in the treatment of diabetes, and the later discovery of and use of sulfonylureas, biguanides and thiazolidenediones, such as troglitazone, rosiglitazone or pioglitazone, as oral hypoglycemic agents, the treatment of diabetes could be improved. The use of insulin typically requires multiple daily doses. Determination of the proper dosage of insulin requires frequent estimations of the sugar in urine or blood. The administration of an excess dose of insulin causes hypoglycemia, with effects ranging from mild abnormalities in blood glucose to coma, or even death. Treatment of non-insulin dependent diabetes mellitus (Type II diabetes, NIDDM) usually consists of a combination of diet, exercise, oral hypoglycemic agents, e.g., thiazolidenediones, and in more severe cases, insulin. However, the clinically available hypoglycemic agents can have side effects that limit their use. In the case of insulin dependent diabetes mellitus (Type I), insulin is usually the primary course of therapy.
U.S. Pat. No. 5,658,944, WO92/10468, WO97/36579, WO98/05331 and WO 00/23407 disclose agents for the treatment of atherosclerosis, obesity and diabetes.
T. Komoto et al., Chem. Pharm. Bull., 48 (12) 1978–1985 (2000), and JP14173426A disclose certain fibrate compounds containing piperidine moieties. International Publication No. WO 93/12086 discloses arylamide derivatives useful for treating and preventing various thromboses, embolisms, arterioscleroses, hypertensions and so forth. International Publication No. WO 02/30896 discloses 2,2-diphenylbutanamide derivatives useful as peripherally acting analgesic and neurogenic pain controller. U.S. Pat. No. 5,411,972 discloses arylamide derivatives for treating hyperlipemia. U.S. Pat. No. 6,362,203 discloses 4-hydroxy-4-phenylpiperidine derivatives having peripheral analgesic action. U.S. Pat. No. 5,994,356 discloses carboxylic acid derivatives having aggregation-inhibiting activity.
International Publication Nos. WO 02/064549 and 02/064139 disclose certain compounds which are PPARα activators.
U.S. Pat. No. 3,801,581 discloses certain α-phenyl-fatty acids substituted by azacycloalkyl residues and their derivatives which are useful as anti-inflammatory and antiphlogistic agents. International Publication No. WO 01/81310 discloses certain 1-aroyl-piperidinyl benzamidines which inhibit Factor Xa or tryptase.
International Publication No. WO 01/90101 discloses arylmethylamine derivatives for use as tryptase inhibitors. International Publication No. WO 01/85716 discloses nitro-substituted 2-piperidone compounds for the treatment of cancer. International Publication No. WO 00/14066 discloses 4,4-biarylpiperidine derivatives with opiod receptor activity. U.S. Pat. No. 6,153,755 discloses a process for preparing piperidine compounds and intermediates therefore.
International Publication No. WO 96/02250A1 discloses haloperidol analogs and their uses. International Publication No. WO 02/28834 discloses processes for the preparation of aryl-piperidine carbinols and intermediates thereof.
U.S. Pat. No. 6,376,494 discloses cycloalkyl-substituted aryl-piperazines, piperidines and tetrahydropyridines as serotonergic agents, which may be useful for the treatment of anxiety, depression, cognitive deficits and prostate cancer. U.S. Pat. No. 6,303,637 discloses heterocyclic potassium channel inhibitors to treat autoimmune disorders, cardiac arrhythmias and the like. U.S. Pat. No. 6,323,229 discloses N-acyl and N-aroyl aralkylamides useful in treating or preventing migraine, depression and other disorders for which a 5-HT1 agonist or antagonist is indicated. U.S. Pat. No. 6,153,758 discloses heteroarylic-arylic diphosphines as chiral catalysts for stereocontrolled reactions.
Published European patent application 0 548 798 discloses a variety of heterocyclic-containing antiviral agents.
International Publication No. WO 93/07141 discloses heterocyclic 3-phenylpyrrolidin-2-ones useful for inhibiting tumor necrosis factor production. International Publication No. WO 92/19594 discloses pyrrolidinone derivatives which inhibit phosphodiesterase IV and tumor necrosis factor (TNF). U.S. Pat. No. 5,420,154 relates to 4-(substituted phenyl)-2-pyrrolidinone derivatives which inhibit the production of tumor necrosis factor (TNF). U.S. Pat. No. 4,476,311 provides analgesic and anti-inflammatory 4-carboxy-pyrrolidin-2-one compounds.
Thus, although there are a variety of anti-atherosclerosis and diabetes therapies, there is a continuing need and a continuing search in this field of art for alternative therapies.